Pedro Pasik

Brainstem pathology in DYT1 primary torsion dystonia

DYT1 dystonia is a severe form of young‐onset dystonia caused by a mutation in the gene that encodes for the protein torsinA, which is thought to play a role in protein transport and degradation. We describe, for the first time to our knowledge, perinuclear inclusion bodies in the midbrain reticular formation and periaqueductal gray in four clinically documented and genetically confirmed DYT1 patients but not in controls. The inclusions were located within cholinergic and other neurons in the pedunculopontine nucleus, cuneiform nucleus, and griseum centrale mesencephali and stained positively for ubiquitin, torsinA, and the nuclear envelope protein lamin A/C. No evidence of inclusion body formation was detected in the substantia nigra pars compacta, striatum, hippocampus, or selected regions of the cerebral cortex. We also noted tau/ubiquitin‐immunoreactive aggregates in pigmented neurons of the substantia nigra pars compacta and locus coeruleus in all four DYT1 dystonia cases, but not in controls. This study supports the notion that DYT1 dystonia is associated with impaired protein handling and the nuclear envelope. The role of the pedunculopontine and cuneiform nuclei, and related brainstem other involved brainstem structures in mediating motor activity and muscle tone also suggest that alterations in these structures, in mediating motor activity and controlling muscle tone suggests that alterations in these structures could underlie the pathophysiology of DYT1 dystonia. Ann Neurol 2004

The Internal Organization of the Neostriatum in Mammals

Publisher Summary This chapter describes the internal organization of the neostriatum in mammals. Biochemical and pharmacological investigations into the nature of extrapyramidal disorders have brought forward the role of the neostriatum as the nodal structure of the basal ganglia system; hence, the paramount importance of unraveling the intricate organization of this nuclear mass. Three types of neurons are present in the cat caudate nucleus, on the basis of size. The medium size cells measuring 9–18 μm comprise over 98% of all neurons. They have a large round and pale nucleus and a narrow rim of pale cytoplasm. A larger version of this type contains Nissl bodies, and the nucleus is indented. The large cells are over 20 μm and represent less than 1% of the population. Their nucleus is indented and large amounts of Nissl bodies are present. The small cells, less than 8 μm in diameter and of similar frequency as the large cells, have rather dark cytoplasm and no Nissl bodies.

The visual world of monkeys deprived of striate cortex: Effective stimulus parameters and the importance of the accessory optic system

Abstract Behavioral and anatomic studies were conducted to define the effective stimulus parameters and the necessary structures for visually guided behavior after complete exclusion of the striate cortex. It was found that operated monkeys mastered several combinations of total luminous flux-equated targets differing in luminance with markedly less errors in successive tests, thus showing a certain degree of brightness constancy. Some of these animals could also learn a triangle vs. circle discrimination, and exhibited signs of color vision. Enlarging the lesions to include most of areas 18 and 19 resulted in monkeys which could not master a brightness and size discrimination in the absence of luminous flux cues. Section of the optic chiasma did not affect the residual luminous flux discrimination whereas destruction of the accessory optic system abolished this capacity. Following eye-enucleations, electron microscopic examination revealed “dark” degeneration without a hyperfilamentous stage in the contralateral and ipsilateral accessory optic nuclei. Findings suggest that monkeys without striate area may still exhibit some of the approximate constancies which allow the perception of a structured visual space, provided that the peristriate and parastriate cortices are relatively preserved. The accessory optic system appears to be necessary for the basic discrimination of total luminous flux. Its nucleus receives crossed and uncrossed optic fibers, and many other non-optic afferents.

Extrageniculostriate vision in the monkey: discrimination of luminous flux-equated figures.

Six monkeys (Macaca mulatta) were tested before and after histologically confirmed total removal of the striate area and complete degeneration of the lateral geniculate nuclei. Using Kluvers pulling-in technique with nonmovable transillu-minated targets, two discrimination problems were given at both a high and a low photometric level. In the first test, the targets were of equal area and differed in luminance and total luminous flux (B-F problem). In the second test, figures differed in luminance and area in an inverse proportion (BA problem) which resulted in their being closely matched for total luminous flux. Postoperatively, the animals showed significant deficits on all tests. Every monkey, however, achieved criterion level of performance not only on the B-F but on the BA problem as well. Performance on the latter test did not change after dilatation of the pupils, or when minimal flux differences were eliminated as cues by making the rewarded target to have the lesser flux in half of the trials and the greater flux in the other half. These findings indicate that monkeys can be trained to discriminate between stimuli equated for total luminous flux after exclusion of the geniculostriate system. Although it is possible that other stimulus parameters are discriminated by such animals, our results do not necessarily negate Kluvers original concept. Indeed, destriated monkeys may still utilize a luminous flux cue to discriminate flux-equated figures through the detection of differences in the rate of change of this parameter during eyes, head and/or body movements.

Extrageniculostriate vision in the monkey. IV. Critical structures for lightvs. no-light discrimination

Abstract The purpose of the study was to determine which brain structures were critical for the capacity to perform a gross luminous flux discrimination in the absence of striate cortex. Fourteen monkeys were trained to a criterion of successful performance, set at 90% correct responses in 30 consecutive trials, on a light vs. no-light discrimination test, using specially designed automatic equipment which allowed predetermination of Gellerman schedules. All monkeys were able to relearn the test after complete bilateral excision of striate cortex and partial ablation of areas 18 and 19 (histologically verified). Additional bilateral lesions of the temporal neocortex, or posterior parahippocampal and retrosplenial allocortex, or pulvinars, or superior colliculi did not interfere significantly with the relearned habit. Instead, when the additional damage involved the superior colliculi and medial pretectum, there was a major discrimination deficit, but eventually these monkeys could reach the criterion level. Only when the lateral pretectal region was included in the latter lesion was there a failure to master the test in 6000 trials of postoperative testing. The effective damage caused bilateral severe degeneration of the nucleus of the accessory optic tract. Findings indicate that the mesodiencephalic junction contains critical structures for extrageniculostriate vision in the monkey and suggest that the accessory optic system could be one main source of visual input for the capacity to perform luminous flux discrimination tests in the absence of striate cortex.

Visual Functions in Monkeys after Total Removal of Visual Cerebral Cortex1

Publisher Summary This chapter presents a detailed account of a study conducted on 82 rhesus monkeys with total bilateral ablation of the striate cortex. This study revealed a wide repertoire of visual functions retained or recovered after surgery. The lateral geniculate nuclei of the destriated monkeys contained viable neurons that were identified as local circuit interneurons with ubiquitous membrane properties for developing presynaptic sites at any region of the cell surface. The results of additional lesions demonstrated the critical role assumed by various structures in the absence of striate cortex. The primate striate cortex has a preeminent role in all types of visual functions, with the exception of pupillary and blink reactions. Some sort of reorganization must occur in other structures after striate resections. These studies have influenced significantly the search for residual capacities in humans with lesions of the geniculostriate system, which have revealed a retention or recovery similar to that shown by experimentally damaged monkeys.

Serotonin-immunoreactivity in the monkey lateral geniculate nucleus

SummarySerotonin-immunoreactivity in the monkey lateral geniculate nucleus appears as a plexus of fine, beaded fibers decreasing in density from magnocellular to parvocellular laminae. Ultrastructurally, these fibers show strictures and dilations, and are filled with dense round particles as well as granular material attached to outer mitochondrial membranes and microtubules. Most of the profiles followed in serial sections lack morphologically defined synapses. The few synapses observed are asymmetric, some with subjunctional dense bodies. This appearance suggests a possible excitatory effect mainly on interneurons which in turn would inhibit principal cells. Serotonin released non-synaptically may block the delivery of transmitters from retinal terminals and/or the receptors for such transmitters, thereby exerting a modulatory depressing action on principal cells.

Synapses between GABA-immunoreactive axonal and dendritic elements in monkey substantia nigra.

gamma-Aminobutyric acid (GABA)-positive elements in the monkey substantia nigra pars reticulata (SNr) were identified using the peroxidase-antiperoxidase immunocytochemical technique with a direct GABA antibody. Light-microscopic examination revealed fine-caliber immunostained fibers piercing the cerebral peduncle and entering the SNr, where they formed a dense plexus. Ultrastructural observations included boutons with densely packed ovoid synaptic vesicles forming synapses with labeled and unlabeled dendritic elements. Most terminals contained small dark mitochondria, although some endings held larger, paler and fewer of these organelles. The synapses observed between GABA-immunoreactive profiles may represent the morphologic basis for disinhibition of pars compacta neurons reported to follow neostriatal or pallidal stimulation.

Vertical optokinetic nystagmus in the split-brain monkey

Abstract Electrooculograms during optokinetic stimulation in the vertical plane were recorded from seven monkeys ( Macaca mulatta ) before and after section of pregeniculate visual pathways or midsagittal division of brain commissures, or both. Section of one optic tract or of the chiasma did not alter the response. Additional cutting of the corpus callosum resulted in a nystagmus of lower frequency and perverted direction with an oblique component toward the side of the visually “deprived” hemisphere. The deficits in the monkeys with section of the optic chiasma appeared only on monocular stimulation. Additional division of massa intermedia, anterior, posterior, habenular, and intercollicular commissures, completely abolished the nystagmus upward. This defect was also present on binocular stimulation of animals with section of the optic chiasma. These findings support the concept that both sides of the brain must receive adequate visual input, either through the classic optic pathway or through the commissures, to result in normal optokinetic nystagmus in the vertical plane. Subcortical commissures, particularly the posterior commissure, may be more related to the oculomotor output since their section affects the response even on binocular stimulation of monkeys with division of both the optic chiama and the corpus callosum. Since optokinetic nystagmus is a most sensitive indicator of the integrity of the oculomotor system, the possibility of defective eye movements should be considered in the interpretation of the results of visual tests in split-brain monkeys.

Amino Acids and N-acetyl-aspartyl-glutamate as Neurotransmitter Candidates in the Monkey Retinogeniculate Pathways

SummaryThe identity of the neurotransmitter(s) in the mammalian retinogeniculate pathway is unclear. To investigate the possibility that some amino acids and certain dipeptides, such as N-acetyl-aspartyl-glutamate (NAAG), fulfill this function, changes in their concentration were measured in the optic tract, and the parvocellular and magnocellular segments of the LGNd of six monkeys (Macaca fascicularis), seven days after right optic tractotomy. The LGNd was studied also in two additional macaques, three months after occipital lobectomy. Tissue was frozen within five minutes of death, regions were dissected with the micropunch technique, and substances were analyzed by HPLC. Optic tractotomy induced significant, large reductions in NAAG, glutamate and aspartate in the optic tract distal to the lesion. Significant decreases in NAAG were also measured in the LGNd, and these changes were apparent in both the parvocellular and magnocellular segments. A small reduction in glutamate reached significance in the parvocellular laminae, and that of aspartate only approached significance in the magnocellular division. Occipital lobectomy produced large declines in aspartate and glutamate in the LGNd. The results of optic tractotomy support the role of NAAG as a neurotransmitter candidate in the monkey retinogeniculate pathways; its significant decrease in both geniculate segments suggests that both P- and M- retinal axons utilize this substance. Although at times the reductions in glutamate or aspartate failed to reach significance, their role cannot be excluded. The findings after occipital lobectomy strongly favor these latter substances as corticogeniculate and/or geniculocortical transmitters.